Manipulating cytochrome P450 enzymes: new perspectives for cancer treatment

Event Abstract Back to Event Manipulating cytochrome P450 enzymes: new perspectives for cancer treatment Stanislav Yanev1* 1 Bulgarian Academy of Sciences, Department of Drug Toxicology, Bulgaria The cytochrome P450 superfamily of hemoproteins are involved in the oxidative metabolism of a wide range of toxic foreign compounds and have a central role in influencing the response of established tumors to anticancer drugs; these enzymes can either activate or deactivate many anticancer drugs. The outcome, in terms of drug activation (i.e., results in cytotoxicity) or deactivation (i.e. no cytotoxicity and potentially resistance), is dependent upon the relative amount and activity of specific CYPs in individual tumor cells. The achievements of the various "omics" scientific trends enable us more successfully to increase efficiency and reduce the toxicity of anticancer agents by selective manipulation of the expression 0and activity of different cytochrome P450s in tumor cells. Localization and Expression of Cytochrome P450 Enzymes in Human Tumors: Well known fact is the presence of metabolically active CYP1B1 in 70% of renal cell carcinomas with no CYP1B1 activity in normal kidney. Over expression of CYP1B1 was found also in tumors of lung, breast, liver, gastrointestinal tract, prostate and bladder. That turns on CYP1B1 as an early-stage tumor marker. CYP2W1 have been identified as having tumor-specific expression. 1. Anticancer Drugs Metabolized by Cytochrome P450 Enzymes. 2. Development of Cytochrome P450-Based Pro-drugs (CYP 1B1 and CYP 1A1, pro-drug analogs of duocarmycin). • Anticancer nitric oxide donors–aryl oximes, N–nitrosamines, N–hydroxyl-guanidines • Phortress – activation by CYP1B1 induction; active for ovarian and breast cancer • Aminoflavone – CYP 1A1 and 1A2 induction • DUM-135 is activated by CYP1B1 to form its active metabolite, DMU-117 (a tyrosine kinaseinhibitor) 3. Bioreductive Anticancer Drugs. AQ4N is activated by CYPs only under hypoxic conditions toform the active topoisomerase inhibitor AQ4. 4. Gene Therapy: Targeting Drug and Enzyme to the Tumor. 5. Cytochrome P450 Enzymes as a Mechanism of Drug Resistance. Increased expression of CYP1B1 in patients with ovarian cancers leads to development of drug resistance to anticancer drugs which are inactivated metabolically by CYP1B1. These are docetaxel, doxorubicin, paclitaxel, mitoxantrone and tamoxifen. 6. Small Molecule Inhibitors to Cytochrome P450s. The use of specific low-molecular-weight chemical inhibitors of CYP1B1 to modulate the cytotoxic profile of these anticancer drugs is still under experimental stage. Examples: a methylated derivative of oxyresveratrol (piceatannol); tetramethyl stilbene; O-demethylation of biochanin A (a principle isoflavonoid found in red clover) by CYP1B1 produce genistein which in turns inhibited the enzyme. 7. Antisense-Based P450 Therapy Further option for inhibiting the metabolism of anticancer drugs at their target site and by this way to increase their clinical efficacy is antisense-based CYP strategies by suppressing or preventing CYP1B1 expression at the site of the tumor. 8. Immune-Based Therapy. ZYC300 is a CYP1B1-based DNA vaccine, design to stimulate the immune system against tumor cells expressing CYP1B1 and is successfully pass phase II trial. 9. Influence of Cytochrome P450 Polymorphisms on Drug Development. Of great importance of future successful development of new anticancer drugs is to define the profile of individual tumors and indentify those CYPs that are overexpressed. The advent of novel technologies such as tissue microarrays and protein chips should facilitate the potential of tailoring patient-specific therapeutic regiments based on individual CYP expression in tumor cells. Keywords: cytochrome P450, Cancer, drugs Conference: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010. Presentation Type: Invited speaker Topic: Xenobiotic metabolism Citation: Yanev S (2010). Manipulating cytochrome P450 enzymes: new perspectives for cancer treatment. Front. Pharmacol. Conference Abstract: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010. doi: 10.3389/conf.fphar.2010.60.00216 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Oct 2010; Published Online: 04 Nov 2010. * Correspondence: Prof. Stanislav Yanev, Bulgarian Academy of Sciences, Department of Drug Toxicology, Sofia, Bulgaria, stanislav_yanev@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Stanislav Yanev Google Stanislav Yanev Google Scholar Stanislav Yanev PubMed Stanislav Yanev Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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